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MEK signaling inhibitor

Dysregulated MAPK signaling is implicated in a wide range of cancers and occurs via multiple mechanisms.1 Abnormal expression or activating mutations in receptors, such as EGFR, may lead to overactive MAPK signaling.2 Additionally, activating K-Ras and B-Raf mutations that are exhibited in a large number of solid tumors lead to overactive MAPK signaling and may confer resistance to chemotherapeutic and targeted agents.1,2

MEK Signaling Inhibitor
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The inhibition of MAPK signaling with agents targeted toward critical proteins in the pathway, such as MEK, has the potential to inhibit growth in a variety of tumor types.3 GDC-0973 is a potent, selective, orally bioavailable small molecule inhibitor of MEK being developed in collaboration with Exelixis, that is designed to bind to MEK in a non-ATP site, resulting in high specificity.3,4 Inhibiting MEK may overcome activating mutations that occur upstream in the MAPK cascade.3

  1. GDC-0973 is a small molecule being developed in collaboration with Exelixis, that, in preclinical studies, potently and selectively inhibits MEK, a key mediator of cell proliferation and survival.3,4

    MEK Vignette 1

  2. GDC-0973 binds to MEK, resulting in inhibition of its kinase activity. As a consequence, the oncogenic signal from cell surface, Ras and Raf, to ERK is interrupted.3,4

    MEK Vignette 2

  3. Sustained inhibition of ERK activation translates into decreased proliferation and induction of apoptosis. In multiple preclinical studies, GDC-0973 has been shown to inhibit cell growth and induce tumor regression.4

    MEK Vignette 3

References:
1.
Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4:937-947.
2.
McCubrey JA, Steelman LS, Chappell WH, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation, and drug resistance. Biochim Biophys Acta. 2007;1773:1263-1284.
3.
Wong K-K. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4:28-35.
4.
Johnston S. XL518, a potent, selective, orally bioavailable MEK1 inhibitor, downregulates the Ras/Raf/MEK/ERK pathway in vivo, resulting in tumor growth inhibition and regression in preclinical models. Presented at: AACR-NCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics; October 22, 2007; San Francisco, CA. Abstract C209.